Rigvir: A cancer "cure" imported from Latvia that cancer patients should avoid

This blog is based in the United States, and I'm an American. Unfortunately, this produces a difficult-to-avoid baked-in bias towards medicine as it is practiced in the US and, to a lesser extent, as it is practiced in the English-speaking world, because English is my language and I can read accounts coming out of English-speaking countries. The same bias exists with respect to pseudo-medicine, with our concentration having been primarily on either quackery that is practiced in the US, UK, Canada, or Australia (and sometimes New Zealand). It's not because I'm not interested in medicine and pseudo-medicine as practiced in non-English-speaking countries. It's just that I tend to lack the tools in terms of language and bloggers with local knowledge to assist me. That's why, whenever I've tried to cover alternative medicine or "integrative medicine" in non-English-speaking countries, such as when I discussed alternative cancer clinics in Germany or the situation with stem cell clinics in Italy (as bad as or worse than in the US), I always feel that I'm missing something. After all, Google Translate often doesn't really provide more than the gist of what a foreign-language article is trying to say.

A dubious Latvian cancer treatment shows up on my radar

Perhaps the language barrier, coupled with its being primarily a treatment from a very small country, is part of the reason why I haven't discussed a new form of dubious cancer treatment known as Rigvir before. It's a form of treatment that has been popularized mainly in Latvia, but is also sold in Armenia and Georgia. This situation has made finding sufficient information about Rigvir, the claims made for it, what it is, and what it supposedly does, rather challenging. After all, I don't speak Latvian, and I don't know anyone who does. (And, no, having a Lithuanian background on my mother's side doesn't help.) I was prodded from my complacency by an article published earlier this month from LSM.lv, "Health ministry defends claimed cancer treatment." Basically, a Latvian news magazine, De Facto, reported earlier this year that multiple Latvian medical associations had written to the Latvian Health Ministry about Rigvir:

Crucially, it [Rigvir] is included on the health ministry's list of reimbursable medicines, meaning public as well as private money is spent on it.

Yet as De Facto revealed, in January three professional medical organizations, including the Latvian Oncology Association, wrote to the Health Ministry expressing concern that research and publications used to establish the credentials of Rigvir treatment were of poor quality and scientifically questionable: for example in one study supposedly comparing the outcomes for two groups of patients, one group used Rigvir and the other did not, with the Rigvir patients doing considerably better than the control group. However, the Rigvir patients also used chemotherapy, while the control group did not, which should have rendered the findings highly dubious.

Oncologists asked that Rigvir be removed from the list of reimbursable medicines and the National Drug Register pending proper clinical data, and also asked for a review of the official guidelines for the treatment of melanoma involving Rigvir.

In February, the health ministry publicly pledged to review the registration of Rigvir and its inclusion in the list of reimbursable medicines. However, De Facto uncovered that a decision to ignore the oncologists' concerns had already been made in the spring.

What most grabbed my attention about this article was the response of Health Minister Anda Čakša to inquiries about why the Health Ministry decided the way it did. It's a response that'll make a skeptic's jaw drop:

"One of the key issues to change anything in drug registration or compensation conditions is clear evidence that the medicine is or is not effective and safe; that there are or are not side effects," Minister of Health Anda Čaksa told De Facto.

"A letter by some social group saying they don't like something - it's just not helpful. Show us data that this medicine does not work for your patients. We don't have anything to react to at the moment," said Health Minister Anda Čakša.

My reaction was predictable: This is exactly backward! It is up to the company selling a product to provide evidence that it does work for the conditions for which it is marketed, not to critics to show that it doesn't work! The article also notes that Rigvir is the fifth top selling prescription medicine in Latvia, with growing sales, which is another reason to be concerned. So is the marketing of Rigvir outside of Latvia. For instance, quack cancer clinic in Mexico that I've discussed before, Hope4Cancer, offers Rigvir, which it describes in glowing terms:

Rigvir®, the world’s first and only non-genetically modified cancer virotherapy agent, is a non-replicative live virus; it is non-pathogenic, and does not reproduce inside the human body or transmit to others. Once introduced in the body, Rigvir® selectively seeks out cancer cells to replicate within, effectively killing the cell in the process.

While virotherapy is only now emerging as a new wave of oncological therapies, Rigvir® has been intensely studied by researchers for over 50 years, passing all phases of clinical trials, and is registered by the International Virotherapy Center in Latvia as a prescription anti-cancer drug. Though registered as a drug, Rigvir offers a completely safe clinical profile, high therapeutic index, absence of side effects, and ability to selectively target cancer cells – making it unlike most available therapeutic agents.

Not surprisingly, according to Hope4Cancer, Rigvir is fantastic for basically all the common cancers: breast cancer, melanoma, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, liver cancer, and more. Never mind that the only cancer for which there is anything resembling evidence—albeit weak evidence—is melanoma. Rigvir's proponents claim that it can treat any cancer! The clinic even goes so far as to claim:

However, given its universal mode of action, it is likely that Rigvir® is effective against a much larger range of cancers that have not been fully studied yet. In fact, at Hope4Cancer, we have used Rigvir® effectively against many cancers not listed here.

It is important to note that since Rigvir® is a defined pharmaceutical entity that has been established through a process of validated studies to qualify as a drug, it does not completely fall into the category of conventional, alternative, or integrative medicine. Instead, Rigvir® represents a completely new paradigm in cancer treatment, and we at Hope4Cancer are proud to offer it to our patients.

No, if Rigvir works, it would be conventional medicine. Viruses that target specific cancers are very much the hot topic now, although results have generally been mixed. The only thing "alternative" about Rigvir is that it is unproven and sold by a quack cancer clinic in Mexico.

Meanwhile, over at the International Virotherapy Center in Latvia, where Rigvir is primarily marketed, there are the sorts of glowing testimonials (complete with a link to the Virotherapy Foundation, which provides even more glowing testimonials) that automatically set my skeptical antennae a'twitching. For instance, here is a woman named Zane who was diagnosed with stage I (yes, stage I) melanoma that was completely surgically excised. Yet Latvian doctors prescribed her "virotherapy" (a.k.a. Rigvir) afterward:

The treatment for stage I melanoma is basically complete surgical excision with an adequate margin of normal tissue around the melanoma, plus examination of the regional lymph nodes through a procedure called a sentinel lymph node biopsy, if the melanoma is stage IB. (Presumably the woman's lymph nodes were negative, or else she would no longer have stage I melanoma. Rather, she'd have at least stage III melanoma.) There is usually no need for any further treatment. Basically, Zane was exposed to "virotherapy" unnecessarily and massively overtreated for her melanoma. Yet she's promoted as a success story, who gushes about how she had feared losing her hair and feeling sick but didn't and how she was able to have a normal baby.

This testimonial is a bit more disturbing:

Basically, it's a British woman named Nadine who had melanoma in 1999 that recurred in 2009. It sounds as though it's been metastatic, but there are no details that would allow a cancer surgeon like me to know where it metastasized to, how rapidly it grew, and other critical information. We learn that Nadine has apparently undergone radiotherapy, chemotherapy, and surgery, along with being a "guinea pig" for experimental vaccine therapies, suggesting that she must have been a subject in at least one clinical trial. She's convinced that Rigvir is helping her, but there's no way to know for sure. Metastatic melanoma is a strange beast among cancers. It can have an incredibly variable course, rapidly growing and killing some patients, and in others exhibiting a much more indolent behavior. Also, excising melanoma metastases can be curative, if they are single or only a few and can be completely excised surgically. Surgical excision of recurrences and metastases could well have prolonged Nadine's life greatly, but insufficient information is given for me even to speculate whether this is the case with her.

Basically, there is no way of knowing whether Rigvir helped Nadine or not, but she's convinced that it did. What's disturbing is the segment near the end, where Nadine urges patients to "seek alternative therapies." Near the end, she also states that the melanoma has metastasized "all over my body," but it's not clear where that means. Organ metastases are much more serious than skin metastases, for instance. Whatever the case, this one woman is not evidence that "virotherapy" works for melanoma.

There's a lot more where that came from.

What is Rigvir?

The Rigvir website describes the treatment thusly:

RIGVIR® - the worlds [sic] first oncolytic virotherapy medicine, which is approved for cancer treatment and introduced in medical practice. RIGVIR® contains a live nonpathogenic ECHO-7 virus that has not been genetically modified.

RIGVIR® is oncotropic and oncolytic virus. It finds and selectively infects tumour cells. Then replicates in tumour cells and destroys them. Both of these processes, oncotropism and oncolysis, are selective for tumour cells and normal healthy cells are minimally if at all affected.

Oncolytic virotherapy with RIGVIR® is safe and effective cancer treatment, which improves time to progression, survival and quality of life of cancer patients.

I perused what passes for a product information sheet. Rigvir is provided as a 2 ml frozen solution of an adapted and selected ECHO-7 virus strain, Picornaviridae family, Enterovirus genus, Enteric Cytopathic Human Orphan (ECHO) type 7, group IV, positive-sense single-stranded RNA virus produced under GMP. The titer is not less than 10⁶ – 10⁸ TCID₅₀/ml. (TCID₅₀ is a measure of active viral particles.) A brief word is in order here. "Orphan" indicates a virus not known to be associated with any disease. (Since the discovery of ECHO viruses, they have been linked with diseases to the point where most ECHO viruses are no longer considered orphan viruses. Even so, the name stuck.) Echoviruses were first isolated from the feces of asymptomatic children in the context of epidemiological studies of polioviruses and are now known to be one of the leading causes of acute febrile illnesses in children. 90% of ECHO virus infections are asymptomatic, but in the 10% that produce symptoms those symptoms can range from mild to severe, depending on the age, gender, and immune status of the host and the subgroup, serotype, and enteroviral strain. We're talking anything from a nonspecific febrile illness to aseptic meningitis to respiratory symptoms to myocarditis.

What I find most implausible about Rigvir is the claim that it attacks only cancer cells and leaves normal cells alone. It takes a look into the history of Rigvir to get an idea where this claim came from.

Aina Muceniece: Discoverer of Rigvir

The story of Rigvir began several decades ago with a Latvian immunologist Professor Aina Muceniece. Discovering unbiased information on Prof. Muceniece and her discovery of Rigvir is damned near impossible these days, because searches on her name will produce a host of links related to laudatory descriptions of Rigvir and/or associated with the International Virotherapy Center. However, one article does describe the origin of Rigvir thusly:

In the 1960s a young scientist named Aina Muceniece discovered a way to use a virus to assist in identifying and marking melanoma cells. Using this discovery, she was able to create a medicinal substance which could possibly increase the life expectancy of melanoma patients when used alongside other therapeutic methods. The substance underwent preliminary studies and was proven to be harmless. These results made it possible for the scientist to use it in the treatment of melanoma, while recording her observations.

Unfortunately, even the unfailing enthusiasm of Aina Muceniece was unable to successfully turn Rigvir (its name honours Riga, the capital of Latvia), into an approved and widely applied treatment. Efficacy studies would have required much larger resources than were available.

A PubMed search on Prof. Muceniece's name doesn't turn up very much, just two Russian language articles and a frequently touted clinical study from 2015, to which her name must have been added posthumously given that she died in 2010 at the age of 85. Of course, given the time period of the discovery of what is now called Rigvir (the height of the Cold War), it is perhaps not too surprising that there are few publications indexed in PubMed about it. Be that as it may, the peer-reviewed English literature is not a good place to find out very much about the origin of Rigvir, although there is a 2012 review article on oncolytic (cancer destroying) viruses that gives some hints. I find this passage rather telling:

Oncolytic activity of ECHO viruses was also studied from the beginning of the 1960s by the group of Dr. Muceniece in the Kirchenstein Institute of Microbiology [59]. The oncolytic activity of natural enterovirus strains was increased by multiple passaging in human tumor cell cultures. Clinical trials of five attenuated oncolytic ECHO enterovirus strains began in 1968. The trials were performed in stage IV cancer patient volunteers, when the conventional therapy had proved inefficient. Viral preparations were administered by intramuscular injections. In some patients, a portion of tumor cells were destroyed that show characteristic cytopathic signs, but the overall therapeutic efficiency was low, supposedly because of the large bulk of the tumor and the rapid development of antiviral immunity. Accordingly, the suggested treatment strategy included radical surgery with subsequent virotherapy for the eradication of residual tumor cells and metastases and the stimulation of antitumor immunity [75].

Based on the results of the trial, ECHO virus strain ECHO-7, which showed the most pronounced oncolytic properties, was selected for further research and named Rigvir [76, 77]. In 1988, phase III clinical trials began, which compared the efficiency of Rigvir with that of surgery and radio- and chemotherapy. In 2004, a patent was issued for Rigvir, and it was officially registered in Latvia, becoming the first enterovirus medication worldwide to complete the full cycle of clinical trials and to be applied in cancer therapy. Since 2008, Rigvir has been available in Latvia as a prescription medication. The information on its properties and usage is available at the site of the Latvian Virotherapy Center (www.viroterapija.lv).

From what I can tell synthesizing the evidence that I've been able to find, Dr. Muceniece made an interesting discovery in the early 1960s in which she observed that some ECHO viruses appeared to have cytolytic effects on tumor cells (i.e., caused them to lyse, or break apart), but the effect was weak, observed in only a few patients, and attenuated by the rapid development of immunity to the virus. In other words, lost in the mists of scientific history, this is an interesting dead end that appeared to go nowhere. Moreover, assuming this account is reasonably accurate, it certainly casts into doubt the stories of "miracle cures" of patients with stage IV cancer, given that those early trials apparently only looked at patients with stage IV cancer and Rigvir didn't work in them. There are anecdotes from surviving contemporaries of Dr. Muceniece that in melanoma Rigvir produced "such excellent results that all medical staff involved were astonished," but no published data, and, pointedly, many of her contemporaries are happy to express their admiration for her but decline to evaluate the medication that she is credited with developing.

Unfortunately, the only primary literature referenced are publications by Dr. Muceniece in Latvian. I searched and could not find any published results of these alleged phase III trials begun in 1988 showing that Rigvir prolongs survival in cancer. Neither could Eduards Ritums, who wrote an extensive article in Latvian translated into English about Rigvir. Ritums notes:

The chain of events should have stopped there. But just a few decades later Rigvir was suddenly included in the list of state-reimbursed medicines and reappeared under new circumstances and in a completely new light, despite the lack of any further trials and contemporaneous developments in similar fields of medical research.

Although Aina Muceniece has passed away, a group of enterprises was formed using her name as a cover. The profits of these enterprises come from the sales of Rigvir and illegitimate advertising, consequently attracting desperate patients from abroad. This medicine is used as treatment not only for melanoma patients, but for other cancer patients as well, and advertised in a way that discredits other currently approved cancer treatment methods. It is unlikely Aina Muceniece would have supported or wanted something like this to happen.

So what evidence is there for Rigvir's anticancer activity? As you will see, it's pretty weak and unconvincing. Even so, somehow Rigvir was approved by the Latvian version of the FDA in 2004 and even more mysteriously found its way onto the list of Latvian state-reimbursed medicines in 2011.

Evidence for Rigvir's anticancer activity: Thin gruel indeed

I did PubMed searches and Google Scholar searches, and, as anyone who tries the same will discover, rapidly found that the published data on Rigvir in the peer-reviewed scientific biomedical literature is incredibly sparse. Ritums notes this in his article:

However, Peteris Alberts, a spokesperson of the Virotherapy Center, referenced many articles in the medical literature (impressing patients who are looking for possible treatment) in an article written by Gunita Nagle titled “Sellers of Hope”, appearing in the Latvian magazine “Ir” [1]: “Are these not studies? We believe they are convincing.” We should mention that doctors obtain information from internationally recognized databases which are compiled by specific search engines, e. g., Medline. These searches return just a few old articles regarding Rigvir. The most recent information the Virotherapy Center can offer are three retrospective case studies. After reading one of the articles, Janis Eglitis asks a rhetorical question: “Did the long-term remission of three patients occur due to Rigvir? No, this story only tells us that three patients used this drug. Unexplained remission in oncology is possible. That can happen either with the use of Rigvir, or anything else – even vitamin C. That does not reflect or prove a trend.” A similar approach is used by authors of self-help books, namely: “I was doing all sorts of things, using anything available, but I believe only this particular something was helpful, so let us all use only this one particular approach!”

Inara Rubene, a pharmaceutical consultant in private practice who has international experience in conducting clinical trials, compares Rigvir’s inclusion in the register of medicinal products with the activities of Ostap Bender (translator’s note: a character from Russian literature, a liar and a boaster, often referred to as ‘the great manipulator’): “The list of clinical trials is absolutely insufficient. Generally recognized phase III trials involving “gold standard” endpoints and overall survival (time to disease progression) are completely absent. Only the great manipulator in his hometown Vasuki would be able to register a medication using such trials.”

Indeed, if you look at the Virotherapy Center's page of clinical studies, you won't be surprised to see how thin it is. The early studies are described thusly glowingly, but without enough detail or evidence to judge how convincing the data are. No mention is made of whether the studies were randomized (I get the impression that they were not), how the cases were matched, and survival rates are reported as ranges, which makes me wonder how on earth the investigators were determining their survival rates. For instance, it is claimed that in melanoma patients the three year survival rate for patients treated with surgery alone was between 46% and 58%, while it was 57% to 84% for those treated with surgery plus Rigvir. I assume that the Virotherapy Center is pooling multiple trials, but this sure isn't any meta-analysis. Without a lot more detail, it's impossible to tell what the investigators did several decades ago.

What about more recent evidence? As Ritums notes, there is nothing more to be found besides three retrospective studies carried out post-registration, as a perusal of the Virotherapy Center's page on its post-registration studies shows. For instance, there is this 2015 study published in Melanoma Research by Donina et al, Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Basically, it is as the title says, a retrospective, unrandomized study that looked at 79 patients who had undergone excision of their primary melanoma and classified as stage IA, IB, IIA, IIB, or IIC according to surgical findings. The rationale was as follows:

Current guidelines for melanoma advise no treatment postsurgery for patients who are classified into substages IB and IIA. Patients in substages IIB and IIC are provided three options: participation in a clinical trial, observation and interferon 7,8. In the absence of strict guidelines, treatment with Rigvir was offered. Thus, 52 study participants received Rigvir and 27 were observed according to the guidelines. The patients who had been treated with interferon were excluded from the present analysis as, in the registry, they were too few to allow for any comparison.

So let me get this straight. This is the rationale? No post-surgical therapy is generally recommended for melanomas Stage IIA and below; so let's just give them Rigvir, instead. This is not a randomized trial. Patients were all offered Rigvir, were treated, and then a retrospective analysis was done after treatment. There was no blinding. There was no evidence of rigorous inclusion criteria. We have no way of knowing whether the Virotherapy Center included all the patients it treated for melanoma of the selected stages during the given time period or if it excluded cases in a way that could bias the results. Also, quite tellingly, no treatment/observation group is, on average, ten years older than the Rigvir group, and has proportionally over twice as many in the stage IIB group, which would have a worse prognosis than earlier stage melanoma. Basically, this study is worthless. I'm disappointed that Melanoma Research, normally a very good journal, published this dreck.

The rest isn't any better. For instance, there is a 2016 paper with three case reports of patients with stage IV melanoma, stage IIIA small cell lung cancer, and a stage IV histiocytic sarcoma, all of whom were treated with Rigvir and all of whom have survived longer than expected. Of course, case reports can be useful for hypothesis generation, but do not generally show efficacy. Another study is listed (but not linked to). It's a retrospective study published in Latvijas Ārsts (Latvian Doctor) that looked at the progression-free period for stage II melanoma patients and observed that patients treated with surgery and observed were 6.7 times more likely to recur than those treated with oncolytic virotherapy after surgery. This study suffers from the same problems as the 2015 study. It's not randomized. It's retrospective. We have no way of knowing how the cases were selected.

All of this leads to the question: Does Rigvir have anticancer activity, particularly against melanoma? My answer is simple: Damned if I know given the lack of valid, rigorous clinical trial evidence, but I tend to doubt it strongly. Rigvir might have weak activity in melanoma (although I doubt even that), but there's no way Rigvir is curing patients with stage IV cancers and it's incredibly unlikely that it is active against the range of cancers for which it is used.

Rigvir is most likely cancer quackery

There are many aspects to the Rigvir story that strongly suggest that Rigvir is probably cancer quackery. First, there is its mysterious origin story. As I read more about Rigvir, I couldn't help but hear echoes of the story of Stanislaw Burzynski, with the exception that there is no evidence of which I'm aware that Dr. Muceniece ever supported the uses to which Rigvir has been put since its registration in Latvia in 2004. The echoes I heard, however, were distinct and came from the lack of information about the origin of this therapy, which goes back even further than the 1970s origin of Stanislaw Burzynski's antineoplastons. True, the parallel is not anywhere near airtight, but it's troubling.

Next, there is the way Rigvir is marketed, which is straight out of the cancer quack playbook. There are slickly produced videos on the International Virotherapy Center website full of appealing patients singing the praises of how Rigvir saved their lives in personal anecdotes and even a foundation that promotes Rigvir, again with glowing testimonials. This is definitely a red flag.

Then there's how the International Virotherapy Center has represented the registration of Rigvir. In brief, it tries very hard to make it sound as though the drug was registered in accordance with European Union standards when it wasn't. Again, Ritums tells the tale:

Rubene is embarrassed that “manipulative patient testimonials are disseminated, and that magazines and newspapers are flooded with promotional articles where Virotherapy Center representatives without any medical education declare Rigvir to be the the [sic] first drug in its group and state there are no similar agents available in the world [2-4]. Rigvir advertising materials also emphasize that this agent was registered in an EU country, thus misleading patients and making them believe that Rigvir was registered according to EU standards, although it is well-known this medication was registered before Latvia joined the European Union. Academic, chemist and Rigvir shareholder Ivars Kalvins (translator’s note: known also as the inventor of meldonium (Mildronate)) [5] keeps asserting without the smallest feeling of guilt that Rigvir is the first-choice agent for the treatment of a “sensitive” tumor [6], even after multiple objections.”

Then, like many dubious clinics, the Virotherapy Center disparages conventional medicine and portrays Rigvir as "natural":

Communications expert (translator’s note: online writer on science and evidence-based medicine) Ksenija Andrijanova emphasizes that the way the Virotherapy Center advertises itself is not typical for a medical facility, even though they are trying very hard to look like one. After exploring fraudulent treatment methods (there are many in oncology), Andrijanova has noticed two common features: “First, conventional treatment approaches are blatantly discredited, especially radiation and chemotherapy since they have side effects (which is true). However, the claim that these therapies do not help and recovery chances are very low is much more dangerous, and it is a false statement. Secondly, there are statements that oncology patients can be treated in a ‘natural way,’ and the real cancer treatment agent is safe, natural and harmless. Both features were present in the Virotherapy Center’s materials.”

Others have noted that Rigvir, when first sold, was inexpensive, but with its growing popularity the price has gone up. A telling quote comes from the Medical Director of the center, Dace Baltina, who was quoted in the magazine Ir as saying, “We do not promise to heal”, but “a patient is ready to pay believing the recovery will happen.” Sound familiar? And that doesn't even take into account the association the Virotherapy Center now has with what is without a doubt a quack clinic in Mexico, Hope4Cancer. As I documented before, in addition to Rigvir, H4C offers high dose intravenous vitamin C, alkalinization, coffee enemas, juice fasting, near infrared saunas, detox routines, and more quackery. None of this has stopped the EU from providing support under Horizon 2020 for a "feasibility" study as a prelude to a phase 2 trial to support registration with the European Medicine Agency. Somehow I doubt Rigvir will make it that far. At least, I sincerely hope that it doesn't, unless of course rigorous clinical trials show that it actually works, which is, based on my reading of the existing data, highly doubtful, albeit not impossible.

What we have in Rigvir is yet another example of alternative medicine co-opting an interesting treatment from history that had been largely abandoned, resurrecting it, and riding it to profits. Immunotherapy, including the use of oncolytic viruses to target cancer, is all the rage these days in oncology; so a treatment like Rigvir is easy to sell based on its supposed immunological mechanism. Never mind that there is such a paucity of evidence that it actually works. Cancer patients, beware.